We are using inbred mouse strains that develop high spontaneous incidences of retrovirally induced leukemia as model systems for identifying new leukemia disease genes. The expectation is that some of these genes will also represent human disease genes that might not be easy to identify directly in humans. Once these genes are identified, we use gene knockout and transgenic mice, genetic criteria, and cell biological approaches to understand how these genes function in disease induction, to place these genes into different biochemical pathways, and to develop new mouse models for human leukemia. The BXH2 and AKXD recombinant inbred strains have been particularly valuable for this research because they develop high incidences of myeloid or B- and T-cell leukemia, respectively, and the proviral integration sites in these leukemias provide powerful genetic tags for disease gene identification. During the past several years, we have identified many new leukemia disease genes in these strains by proviral tagging. Importantly, some of these genes are also involved in human leukemia, validating the usefulness of this approach for human disease gene identification. Despite this success, however, it is apparent that there are many more disease genes to be identified. During the past year, we developed an inverse PCR (IPCR) method for proviral tagging that makes use of automated DNA sequencing and the genetic tools provided by the Mouse Genome Project, thereby increasing the throughput for disease gene identification. We also used this IPCR method to clone and analyze more than 400 proviral integration sites from BXH2 and AKXD leukemias and, in the process, identify more than 90 new candidate leukemia disease genes. Some of these genes appear to function in pathways already implicated in leukemia, whereas others are likely to define new disease pathways. Our studies highlight the power of the mouse as a tool for gene discovery and functional genomics in the modern genome era. Future studies will validate the role of these genes in leukemia and determine whether any are involved in human disease.